The invention in its broad aspects relates to caprylolactam derivatives which are useful as angiotensin converting enzymme inhibitors and as antihypertensives. The compounds of this invention can be shown by the following formula: ##STR1## wherein R and R.sup.3 are the same or different and are
hydroxy, PA1 lower alkoxy, PA1 lower alkenoxy, PA1 aryloxy such as phenoxy, PA1 arloweralkoxy, such as benzyloxy; PA1 hydrogen, PA1 alkyl of from 1 to 12 carbon atoms which include branched and cyclic and unsaturated (such as allyl) alkyl groups, PA1 substituted loweralkyl wherein the substituent(s) can be halo, lower alkoxy, hydroxy, aryloxy (such as phenoxy), amino, lower alkylamino, aminoloweralkylthio, aminolower alkoxy, diloweralkylamino, acylamino, (such as acetamido and benzamido), arylamino, (such as phenylamino), guanidino, phthalimido, mercapto, loweralkylthio, arylthio (such as phenylthio), carboxy, carboxamido or carboloweralkoxy, PA1 arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl (such as benzyl, styryl, indolylethyl, imidazolylmethyl, naphthylethyl), PA1 substituted arloweralkyl, or substituted heteroarlower alkyl, wherein the aryl or heteroaryl substituents are halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, phenyloxy, acylamino, diloweralkylamino, loweralkylamino, carboxyl, haloloweralkvl, acyl or aroyl; PA1 arloweralkyl or heteroarloweralkyl substituted on the alkyl portion bv amino, hydroxyl or acylamino;
R.sup.1 is PA0 R.sup.2 and R.sup.4 are hydrogen or lower alkyl; and, the pharmaceutically acceptable salts thereof. PA0 alkyl denotes straight and branched hydrocarbons of C.sub.1 -C.sub.12 and loweralkyl denotes straight and branched hydrocarbons of C.sub.1 -C.sub.8 ; PA0 alkenyl denotes straight and branched hydrocarbons of C.sub.2 -C.sub.12 and loweralkenyl denotes straight and branched hydrocarbons of C.sub.2 -C.sub.8, each of which contain a double bond; PA0 alkynyl denotes straight and branched hydrocarbons of C.sub.2 -C.sub.12 and loweralkynyl denotes straight and branched hydrocarbons of C.sub.2 -C.sub.8, each of which contain a triple bond; PA0 aryl and the prefix "ar" denote unsubstituted aromatic ring or rings of C--C such as, for example, phenyl, naphthyl, biphenyl; PA0 acyl denotes a carboxylic acid derivative represented by the formula ##STR2## wherein R is alkane, aralkane, arene, heteroarene, heteroaralkene, and substituted derivatives thereof so that acyl denotes, for example, alkanoyl, aroyl, aralkanoyl, heteroaryl, heteroaralkanoyl, and the like; PA0 cycloalkyl denotes an unsubstituted alkyl ring of C.sub.3 -C.sub.10 ; PA0 hetero denotes the heteroatoms N, O PA0 heteroaryl denotes an aryl group containing a heteroatom; PA0 heterocycle denotes a saturated or unsaturated aromatic or non-aromatic cyclic compound containing a heteroatom; PA0 halogen and halo denote F, Br, Cl or I atoms; and, PA0 alkoxy denotes a C.sub.1 -C.sub.6 alkyl with O. PA0 R and R.sup.3 are independently hydroxy, lower alkoxy, or benzyloxy; PA0 R.sup.1 is alkyl having from 1 to 8 carbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, acylamino, hydroxy, aminoloweralkylthio, aminoloweralkoxy, arlylthio, aryloxy or arylamino, aralkyl or heteroaralkyl wherein the alkyl portion has 1 to 3 carbon atoms (such as phenethyl or indolylethyl) or substituted arloweralkyl (phenyl lower alkyl or naphthyl lower alkyl) and substituted heteroarloweralkyl wherein the alkyl groups have 1-3 carbons optionally substituted with amino, hydroxy, or acylamino and wherein the substituents on the aryl or heteroaryl group are halo, dihalo, amino, aminoalkyl, hydroxy, lower alkoxy, lower alkyl, phenoxy or benzoyl; PA0 R.sup.2 and R.sup.4 are hydrogen or lower alkyl. PA0 R.sup.2 is hydrogen or lower alkyl; PA0 R.sup.4 is hydrogen; PA0 R.sup.1 is alkyl from 1 to 8 carbon atoms, phenyl lower alkyl, indolyl lower alkyl, halo phenyl lower alkyl, phenoxy lower alkyl, amino lower alkyl, phenyl thio lower alkyl, aminoethylthio lower alkyl, aminoethyloxy lower alkyl; PA0 R and R.sup.3 are independently hydroxy, lower alkoxy, benzyloxy. PA0 R.sup.2 and R.sup.4 are hydrogen; PA0 R.sup.1 is phenyl lower alkyl, indolyl lower alkyl, halophenyl lower alkyl, amino lower alkyl; PA0 R and R.sup.3 are independently hydroxy, lower alkoxy or benzyloxy. PA0 hydrochlorothiazide (10-200 mg), timolol (5-60 mg), methyl dopa (65-2000 mg), the pivaloyloxyethyl ester of methyl dopa (30-1000 mg), indacrinone and variable ratios of its enantiomers (25-150 mg) and (+)-4-{3{-[2-(1-hydroxycyclohexyl)-ethyl]-4-oxo-2-thiazolidiny}propyl}-ben zoic acid (10-100 mg).
As used throughout this application, including the claims, and unless specified otherwise:
Exemplary loweralkyl or lower alkenyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like, and exemplary aralkyl groups include, for example, benzyl, p-methoxybenzyl and the like. Illustrative heteroaryl groups include, for example, pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl thiazolyl and quinolinyl.
Preferred are those compounds of Formula I wherein:
More preferred are compounds of Formula I wherein
Most preferred are compounds of Formula I wherein
The preferred, more preferred and most preferred compounds also include the pharmaceutically acceptable salts thereof.
The products of Formula (I) and the preferred subgroups can be produced by one or more of the methods and subroutes depicted in the following equations. The definitions of R, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same as in Formula (I) except where noted. ##STR3##
The perhydroazonin-2-one (II), prepared from cycloactenone by the procedure of Blicke et al., [J. Am. Chem. Soc., 76, 2317 (1954)] or from a substituted cyclooctenone as described by Wilson, et. al., J. Org. Chem., 44, 330 (1979) followed by catalytic hydrogenation, is converted to (III) with PX.sub.5 (X=CL or Br) [Nagasawa et al., J. Med. Chem., 14, 501 (1971)]. Reaction of (III) with an iodoester (IV) in the presence of a strong base, such as sodium hydride, in a suitable solvent like DMF or THF affords (V). Treatment of (V) with an azide salt, such as lithium azide, in a solvent, like DMF, gives (VI) which upon reduction with hydrogen and a catalyst such as palladium produces amine (VII). Reductive amination of an .alpha.-keto ester or acid (VIII) with amine (VII) using sodium cyanoborohydride or hydrogen and a suitable catalyst such as palladium or Raney nickel in a suitable solvent, such as ethanol, affords (I).
Groups R and R.sup.3 can be modified by known methods, if desired. For example, if R=OEt and R.sup.3 =O--t--Bu, the diester (I) can be converted to the monoester, R.sup.3 =OH, by treatment with trifluoroacetic acid. If R=R.sup.3 =OEt or R.sup.3 =OH and R=OEt, for example, (I) can be converted to the diacid R=R.sup.3 =OH by basic hydrolysis. Alternatively (III) can be converted to azide (IX) as described above. Reaction of (IX) with (IV) as described above affords (VI) which can be converted to (I) by the described methods.
The starting materials which are required for the above processes herein described are known in the literature or can be made by known methods from known starting materials.
In products of general Formula (I), the carbon atom to which, R.sup.1, R.sup.2 and R.sup.4 are attached and the ring carbon atom to which the fragment ##STR4## is attached are asymmetric (R.sup.1, R.sup.2 and R.sup.4 .noteq.H). The compounds accordingly exist in diastereoisomeric forms or as enantiomers, or in mixtures thereof. The above described syntheses can proceed through racemates, enantiomers or diastereomers. When diastereomeric products result from the synthetic procedures, the diastereomeric products can be separated by chromatographic or fractional crystallization methods. When racemic products result, they may be resolved by crystallization of salts of optically active acids or bases or by other methods known in the art. The part-structures, ##STR5## of Formula (I) can be in two configurations (S or R) and both are within the scope of this invention although S is generally preferred except at the carbon atom to which R.sup.4 is attached.
The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine and the like. Also salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic acids. The non-toxic physiologically acceptable salts are particularly valuable, although other salts are also useful, e.g., in isolating or purifying the product.
The salts may be formed by conventional means, as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.
The compounds of this invention inhibit angiotensin converting enzyme and thus block conversion of the decapeptide angiotensin I to angiotensin II. Angiotension II is a potent pressor substance. Thus blood-pressure lowering results from inhibition of its biosynthesis especially in animals and humans whose hypertension is angiotensin II related. Furthermore, converting enzyme degrades the vasodepressor substance, bradykinin. Therefore, inhibitors of angiotensin converting enzyme may lower blood pressure also by potentiation of bradykinin. Although the relative importance of these and other possible mechanisms remains to be established, inhibitors of angiotensin converting enzyme are effective antihypertensive agents in a variety of animal models and are useful clinically, for example, in many human patients with renovascular, malignant and essential hypertension. See, for example, D. W. Cushman et al., Biochemistry 16, 5484 (1977).
The evaluation of converting enzyme inhibitors is guided by in vitro enzyme inhibition assays. For example, a useful method is that of Y. Piquilloud, A. Reinharz and M. Roth, Biochem. Biophys. Acta, 206, 136 (1970) in which the hydrolysis of carbobenzyloxyphenylalanylhistidinylleucine is measured. In vivo evaluations may be made, for example, in normotensive rats challenged with angiotensin I by the technique of J. R. Weeks and J. A. Jones, Proc. Soc. Exp. Biol. Med., 104, 646 (1960) or in a high renin rat model such as that of S. Koletsky et al., Proc. Soc. Exp. Biol. Med., 125, 96 (1967).
Thus, the compounds of this invention are useful as antihypertensives in treating hypertensive mammals, incuding humans and they can be utilized to achieve the reduction of blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. The compounds of this invention can be administered to patients in need of such treatment in a dosage range of 1.0 to 100 mg oer patient optionally given several times, thus giving a total daily dose of from 1.0 to 400 mg per day. The dose will vary depending on severity of disease, weight of patient and other factors which a person skilled in the art will recognize.
Also, the compounds of this invention may be given in combination with diuretics or other antihypertensives. Typically these are combinations whose individual per day dosages range from one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. To illustrate these combinations, one of the antihypertensives of this invention effective clinically in the range 2.5-100 milligrams per day can be effectively combined at levels ranginq from 0.5-100 milligrams per day with the following antihypertensives and diuretics in dose ranges per day as indicated:
In addition, the triple drug combinations of hydrochlorothiazide (15-200 mg) plus amiloride (5-20 mg) plus converting enzyme inhibitor of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol (5-50 mg) plus the converting enzyme inhibitor of this invention (3-200 mg) are effective combinations to control blood pressure in hypertensive patients.
The above dose ranges will be adjusted on a unit basis as necessary to permit divided daily dosage. Also, the dose will vary depending on the severity of the disease, weight of patient and other factors which a person skilled in the art will recognize.
Typically the compounds and combinations shown above are formulated into pharmaceutical compositions as discussed below.
About 1.0 to 100 mg of a compound or of Formula I or a physiologically acceptable salt thereof or a mixture with diuretic and/or other antihypertensive compounds is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc. or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.